Abstract The most deadly characteristic of cancer cells is to invade local tissues and establish productive niches outside of the primary tumor site wherein proliferative responses are re-engaged within the specialized confines of the 3-dimensional (3D) extracellular matrix. Current evidence indicates that extravasating cancer cells may reside within distant tissues in a dormant state awaiting further genetic or epigenetic events before initiating proliferative activity. However, the molecular mechanisms that support the re-engagement of proliferative programs in 3D matrix environments remain undefined. Using newly developed conditional knockout models of the membrane-anchored matrix metalloproteinases, MT1-MMP and/or MT2-MMP, we describe new studies demonstrating that these proteolytic enzymes control the post-extravasation, 3D growth of cancer cells by remodeling the surrounding extracellular matrix and activating a YAP/TAZ mechanotransduction axis that controls proliferative responses following the RalA/exocyst-dependent mobilization of the metalloproteinases to the cell surface. Concurrently, MT-MMPs are also unexpectedly routed to the cancer cell nuclear compartment where they also impact proliferation programs by exerting direct transcriptional control of cellular functions. Given these preliminary findings, we outline plans for molecular and cellular studies that seek to i) characterize the role of RalA-exocyst axis regulating MT-MMP trafficking to the cell surface, ii) define the role of the MT- MMP/YAP-TAZ mechanotransduction axis in regulating cancer cell behavior and iii) characterize MT-MMP nuclear trafficking as a novel regulatory hub for controlling cancer cell transcriptional responses. These studies should provide new insights into the role of the MT-MMPs in controlling the behavior of cancer cell populations growing within the 3D extracellular matrix and lead to the identification of novel targets for therapeutic intervention.